Kobayashi Sumitaka, Sata Fumihiro, Miyashita Chihiro, Miura Ryu, Azumi Kaoru, Kobayashi Sachiko, Goudarzi Houman, Araki Atsuko, Ishizuka Mayumi, Todaka Takashi, Kajiwara Jumboku, Hori Tsuguhide, Kishi Reiko
Center for Environmental and Health Sciences, Hokkaido University, North-12, West-7, Kita-ku, Sapporo, Hokkaido 060-0812, Japan.
Center for Environmental and Health Sciences, Hokkaido University, North-12, West-7, Kita-ku, Sapporo, Hokkaido 060-0812, Japan; Health Center, Chuo University, 42-8, Ichigaya-Hommura-cho, Shinjuku-ku, Tokyo 162-8473, Japan.
Toxicology. 2017 Sep 1;390:135-145. doi: 10.1016/j.tox.2017.08.010.
Associations between prenatal exposure to polychlorinated biphenyls (PCBs) and reduced birth-size, and between DNA methylation of insulin-like growth factor-2 (IGF-2), H19 locus, and long interspersed nuclear element-1 (LINE-1) and reduced birth-size are well established. To date, however, studies on the associations between prenatal exposure to PCBs and alterations in methylation of IGF-2, H19, and LINE-1 are lacking. Thus, in this study, we examined these associations with infant-gender stratification.
We performed a prospective birth cohort study using the Sapporo cohort from the previously described Hokkaido Birth Cohort Study on Environment and Children's Health conducted between 2002 and 2005 in Japan. In the final 169 study participants included in this study, we measured the concentrations of various non-dioxin-like PCBs in maternal blood during pregnancy using high-resolution gas chromatography/high-resolution mass spectrometry. IGF-2, H19 and LINE-1 methylation levels in cord blood were measured using the bisulfite pyrosequencing methods Finally, we assessed the associations between prenatal exposure to various PCBs and the gene methylation levels using multiple regression models stratified by infant gender.
We observed a 0.017 (95% confidence interval [CI]: 0.003-0.031) increase in the log-transformed H19 methylation levels (%) in cord blood for each ten-fold increase in the levels of decachlorinated biphenyls (decaCBs) in maternal blood among all infants. Similarly, a 0.005 (95% CI: 0.000-0.010) increase in the log-transformed LINE-1 methylation levels (%) in cord blood was associated with each ten-fold increase in heptachlorinated biphenyls (heptaCBs) in maternal blood among all infants. In particular, we observed a dose-dependent association of the decaCB levels in maternal blood with the H19 methylation levels among female infants (P value for trend=0.040); likewise a dose-dependent association of heptaCB levels was observed with LINE-1 methylation levels among female infants (P value for trend=0.015). Moreover, these associations were only observed among infants of primiparous women.
Our results suggest that the dose-dependent association between prenatal exposure to specific non-dioxin-like PCBs and increases in the H19 and LINE-1 methylation levels in cord blood might be more predominant in females than in males.
孕期暴露于多氯联苯（PCBs）与出生体重降低之间的关联，以及胰岛素样生长因子-2（IGF-2）、H19基因座和长散在核元件-1（LINE-1）的DNA甲基化与出生体重降低之间的关联已得到充分证实。然而，迄今为止，关于孕期暴露于PCBs与IGF-2、H19和LINE-1甲基化改变之间关联的研究尚缺。因此，在本研究中，我们按婴儿性别分层研究了这些关联。
我们使用来自先前描述的北海道环境与儿童健康出生队列研究的札幌队列进行了一项前瞻性出生队列研究，该研究于2002年至2005年在日本开展。在本研究纳入的最终169名研究参与者中，我们使用高分辨率气相色谱/高分辨率质谱法测量了孕期母血中各种非二噁英类PCBs的浓度。使用亚硫酸氢盐焦磷酸测序法测量脐血中IGF-2、H19和LINE-1的甲基化水平。最后，我们使用按婴儿性别分层的多元回归模型评估了孕期暴露于各种PCBs与基因甲基化水平之间的关联。
在所有婴儿中，母血中十氯联苯（decaCBs）水平每增加10倍，脐血中H19甲基化水平（%）的对数转换值增加0.017（95%置信区间[CI]：0.003 - 0.031）。同样，在所有婴儿中，母血中七氯联苯（heptaCBs）水平每增加10倍，脐血中LINE-1甲基化水平（%）的对数转换值增加0.005（95%CI：0.000 - 0.010）。特别是，我们观察到母血中decaCB水平与女婴H19甲基化水平呈剂量依赖性关联（趋势P值 = 0.040）；同样，观察到母血中heptaCB水平与女婴LINE-1甲基化水平呈剂量依赖性关联（趋势P值 = 0.015）。此外，这些关联仅在初产妇的婴儿中观察到。
我们的结果表明，孕期暴露于特定非二噁英类PCBs与脐血中H19和LINE-1甲基化水平增加之间的剂量依赖性关联在女性中可能比男性更显著。
